A primary focus of our work has been on mechanisms of physical and emotional stress and their relevance to major psychiatric and endocrine disorders. Our recent work with corticotropin releasing hormone (CRH) illustrates our comprehensive approach to this area of inquiry. For instance, we have advanced data which indicate that CRH is of physiological relevance to human pituitary-adrenal function, demonstrated its role in the pathophysiology of hypercortisolism in depression and anorexia nervosa, and administered it as a clinically useful means of determining the differential diagnosis between depression and Cushing's disease. Our data regarding interactions between the CRH system and the locus ceruleus-norepinephrine system suggest that a positive feedback loop between these two major effectors of the stress response may account for many of the clinical and biochemical manifestations of melancholic depression. As indirect support for a role of CRH in the mood component of depression, we have shown that procaine produces dose-dependent activation of pituitary-adrenal function in association with mood changes in patients with affective illness. Moreover, in vitro studies show procaine-induced dose-dependent activation of the CRH neuron which is prevented by carbamazepine. In clinical studies with volunteers and patients with panic disorder, we have implicated CRH in exercise and lactate-induced panic and have advanced in vivo and in vitro data that alprazolam may exert therapeutic effects by suppressing the CRH neuron. In studies exploring the mechanisms by which the immune system may stimulate adrenal corticosteroid counterregulation of the immune response, we have shown that both interleukin-I and interleukin-II produce dose-dependent activation of the CRH neuron.